Solution structure of multi-domain protein ER-60 studied by aggregation-free SAXS and coarse-grained-MD simulation

Multi-domain proteins (MDPs) show a variety of domain conformations under physiological conditions, regulating their functions through such conformational changes. One of the typical MDPs, ER-60 which is a protein folding enzyme, has a U-shape with four domains and is thought to have different domain conformations in solution depending on the redox state at the active centres of the edge domains. In this work, an aggregation-free small-angle X-ray scattering revealed that the structures of oxidized and reduced ER-60 in solution are different from each other and are also different from those in the crystal. Furthermore, structural modelling with coarse-grained molecular dynamics simulation indicated that the distance between the two edge domains of oxidized ER-60 is longer than that of reduced ER-60. In addition, one of the edge domains has a more flexible conformation than the other

Genetics of Endometrial Cancers

Endometrial cancers exhibit a different mechanism of tumorigenesis and progression depending on histopathological and clinical types. The most frequently altered gene in estrogen-dependent endometrioid endometrial carcinoma tumors is PTEN. Microsatellite instability is another important genetic event in this type of tumor. In contrast, p53 mutations or Her2/neu overexpression are more frequent in non-endometrioid tumors. On the other hand, it is possible that the clear cell type may arise from a unique pathway which appears similar to the ovarian clear cell carcinoma. K-ras mutations are detected in approximately 15%–30% of endometrioid carcinomas, are unrelated to the existence of endometrial hyperplasia. A β-catenin mutation was detected in about 20% of endometrioid carcinomas, but is rare in serous carcinoma. Telomere shortening is another important type of genomic instability observed in endometrial cancer. Only non-endometrioid endometrial carcinoma tumors were significantly associated with critical telomere shortening in the adjacent morphologically normal epithelium. Lynch syndrome, which is an autosomal dominantly inherited disorder of cancer susceptibility and is characterized by a MSH2/MSH6 protein complex deficiency, is associated with the development of non-endometrioid carcinomas

Histone variant H2A.B-H2B dimers are spontaneously exchanged with canonical H2A-H2B in the nucleosome

精子形成に重要なヒストンによるDNAの新たな折りたたみを解明. 京都大学プレスリリース. 2021-02-22.H2A.B is an evolutionarily distant histone H2A variant that accumulates on DNA repair sites, DNA replication sites, and actively transcribing regions in genomes. In cells, H2A.B exchanges rapidly in chromatin, but the mechanism has remained enigmatic. In the present study, we found that the H2A.B-H2B dimer incorporated within the nucleosome exchanges with the canonical H2A-H2B dimer without assistance from additional factors, such as histone chaperones and nucleosome remodelers. High-speed atomic force microscopy revealed that the H2A.B nucleosome, but not the canonical H2A nucleosome, transiently forms an intermediate “open conformation”, in which two H2A.B-H2B dimers may be detached from the H3-H4 tetramer and bind to the DNA regions near the entry/exit sites. Mutational analyses revealed that the H2A.B C-terminal region is responsible for the adoption of the open conformation and the H2A.B-H2B exchange in the nucleosome. These findings provide mechanistic insights into the histone exchange of the H2A.B nucleosome

Maternal swimming at Misasa Hospital Of Okayama University Medical School First report. Recognition of the pregnant women to maternity swimming

妊婦のスポーツに対する考え方は近年まで比較的消極的であったが，最近マスコミに取り上げられるようになり，妊婦水泳・エアロビクスダンス等は全国的にもかなり普及していると思われる。今回外来通院患者を対象に妊婦水泳に関するアンケート調査を行った結果，大多数のものが関心を持ち，また実施希望を持っていることが判明したのでその概要を報告する。The sports have been contraindication for pregnant women till resent years. Since Dr. Murooka reported the safety and the effectiveness of maternity swimming in 1978. maternity swimming have been taken up and fasionarised by mass media. And then maternity swimming becomes popular in our all over the country. Now we made inquiries about maternity swimming to 25 pregnant women in our outpatients clinic. (Results) 1. Eightyfour percent of them were interested in maternity swimming. 2. Eightyeight percent of them wanted to swim. 3. Most of them had little knowledge about tocological effectiveness of maternity swimming. (Conclusion) It is nessesary that the enlightenment and the active management of maternity swimming by obstetricians

Overexpression of DNA Polymerase ζAffects Cisplatin Resistance in Ovarian Cancer: An Immunohistochemical Study

DNA polymerase ζ (Pol ζ) participates in translesional bypass replication. Pol ζ has been shown to be an important contributor to cis-diamminedichloroplatinum (II)(DDP; cisplatin) -induced genomic instability and the subsequent emergence of resistance in vitro. We immunohistochemically examined the expression of Pol ζ in ovarian cancer tissues to determine whether its expression affects the DDP resistance of human ovarian cancers and also to determine whether Pol ζ expression is a prognostic factor for ovarian cancers. We assessed 76 archival, formalin-fixed, paraffin-embedded tissue samples obtained from patients with epithelial ovarian cancers who underwent their first operation between 2003 and 2011. An ovarian cancer tissue array was also used in this study. Immunohistochemical staining of Pol ζ was performed using an anti-human Pol ζ monoclonal rabbit antibody. The strength of expression of Pol ζ was compared with the DDP resistance and clinical features of the study population. The Pol ζ over-expression in ovarian cancer tissue which compared with epithelial cells in normal ovaries was not affected by the histological types, FIGO stage, or patient age, but Pol ζ was significantly more overexpressed in the DDP-resistant group than in the DDP-sensitive group (P = 0.043). Pol ζ over-expression did not significantly affect the survival rate of the ovarian cancer patients; however, the Pol ζ positive group tended to have a poorer long-term prognosis. In conclusion, ovarian carcinoma patients with Pol ζ over-expression are likely to be resistant to DDP, especially in cases of recurrent disease. These results confirm the previous findings in vitro, wherein Pol ζ modulated the cytotoxicity and mutagenicity of DDP

Elucidation of the mechanism of subunit exchange in αB crystallin oligomers

AlphaB crystallin (αB-crystallin) is a key protein for maintaining the long-term transparency of the eye lens. In the eye lens, αB-crystallin is a “dynamical” oligomer regulated by subunit exchange between the oligomers. To elucidate the unsettled mechanism of subunit exchange in αB-crystallin oligomers, the study was carried out at two different protein concentrations, 28.5 mg/mL (dense sample) and 0.45 mg/mL (dilute sample), through inverse contrast matching small-angle neutron scattering. Interestingly, the exchange rate of the dense sample was the same as that of the dilute sample. From analytical ultracentrifuge measurements, the coexistence of small molecular weight components and oligomers was detected, regardless of the protein concentration. The model proposed that subunit exchange could proceed through the assistance of monomers and other small oligomers; the key mechanism is attaching/detaching monomers and other small oligomers to/from oligomers. Moreover, this model successfully reproduced the experimental results for both dense and dilute solutions. It is concluded that the monomer and other small oligomers attaching/detaching mainly regulates the subunit exchange in αB-crystallin oligomer

Dynamics of proteins with different molecular structures under solution condition

Incoherent quasielastic neutron scattering (iQENS) is a fascinating technique for investigating the internal dynamics of protein. However, low flux of neutron beam, low signal to noise ratio of QENS spectrometers and unavailability of well-established analyzing method have been obstacles for studying internal dynamics under physiological condition (in solution). The recent progress of neutron source and spectrometer provide the fine iQENS profile with high statistics and as well the progress of computational technique enable us to quantitatively reveal the internal dynamic from the obtained iQENS profile. The internal dynamics of two proteins, globular domain protein (GDP) and intrinsically disordered protein (IDP) in solution, were measured with the state-of-the art QENS spectrometer and then revealed with the newly developed analyzing method. It was clarified that the average relaxation rate of IDP was larger than that of GDP and the fraction of mobile H atoms of IDP was also much higher than that of GDP. Combined with the structural analysis and the calculation of solvent accessible surface area of amino acid residue, it was concluded that the internal dynamics were related to the highly solvent exposed amino acid residues depending upon protein’s structure

Questionnaire survey on the continuity of home oxygen therapy after a disaster with power outages

AbstractBackgroundAfter the Great East Japan Earthquake, oxygen-dependent patients in areas experiencing power outages could not continue home oxygen therapy (HOT) without oxygen cylinders. The purpose of this study was to examine use of oxygen cylinders in areas experiencing power outages and the effects of HOT interruption on patients' health.MethodsQuestionnaires were mailed to 1106 oxygen-dependent patients and HOT-prescribing physicians in Akita, near the disaster-stricken area. We investigated patients' actions when unable to use an oxygen concentrator and classified the patients based on oxygen cylinder use. Patients who experienced an interruption of or reduction in oxygen flow rate by their own judgment were assigned to the “interruption” and “reduction” groups, respectively; those who maintained their usual flow rate were assigned to the “continuation” group. Differences were tested using analysis of variance and the χ2 tests.ResultsIn total, 599 patients responded to the questionnaire. Oxygen cylinders were supplied to 574 patients (95.8%) before their oxygen cylinders were depleted. Comparison of the continuation (n=356), reduction (n=64), and interruption (n=154) groups showed significant differences in family structure (p=0.004), underlying disease (p=0.014), oxygen flow rate (p<0.001), situation regarding use (p<0.001), knowledge of HOT (p<0.001), and anxiety about oxygen supply (p<0.001). There were no differences in changes in physical condition.ConclusionsMost patients could receive oxygen cylinders after the disaster. Some patients discontinued their usual oxygen therapy, but their overall health status was not affected